HIV causes distinct pathology and immunologic dysregulation at multiple tissue sites throughout the body. While HIV virus itself initiates these events the prolonged state of systemic immune activation seen in HIV- infected individuals likely drives much of the observed immune dysfunction. Within gut associated lymphoid tissue (GALT), HIV mediates the loss/dysfunction of key immune cells leading to increased levels of bacterial products in the blood, which contribute to the sustained immune hyper-activation. The key role of macrophages for detecting microbial products via toll-like receptors (TLRs) and their ability to produce cytokines involved in activation of immune responses make these cells likely key players in this immune pathology. In particular, Kupffer cells are liver macrophages that will be the first to encounter any bacterial products that traverse the gut mucosa (via the portal vein), and the major focus of this proposal will be to investigate the potential for Kupffer cell dysfunction to contribute to the elevated levels of bacterial products and inflammatory cytokines. The simian immunodeficiency virus (SIV)-macaque model has been utilized to provide insights into Kupffer cell function through the identification of viral proteins associated with hyperplasia hypertrophy, multinuclear giant cell formation and inflammatory cytokine production of Kupffer cells. In this proposal we combine the individual strengths of two laboratories, the Sodora laboratory with expertise in SIV non-human primate models and the Crispe laboratory with expertise in liver immunology. We will focus on the Kupffer cell bed located in the sinusoids of the liver, as these are the first population of innate immune cells to see portal vein bacterial products, and produce inflammatory cytokines. We hypothesize that systemic immune activation results in part from the production of inflammatory cytokines by liver macrophages (Kupffer cells). And that therapeutic control of the inflammatory response of Kupffer cells can reduce the level of systemic immune activation and signs of SIV disease progression in pigtail macaques. Our first aim will assess the activation state of liver Kupffer cells obtained at necropsy from uninfected versus SIV infected pigtail macaques. Our second aim will mechanistically assess the role of the NF-kB pathway (stimulated by viral and bacterial products) by suppressing this inflammatory response in Kupffer cells of pigtail macaques utilizing an NF-kB inhibitor. CAPE (Caffeic Acid Phenethylester) prevents the translocation of NF-kB to the nucleus and CAPE infused in polyketal particles are preferentially taken up by Kupffer cells. These studies build on work by Dr. Crispe's laboratory utilizing CAPE-polyketal particles to assess Kupffer cell function of mice. This exploratory R21 is designed to provide insights into the understudied field of liver and Kupffer cell biology with regard to SIV pathogenesis. Through an inhibition of liver macrophage activation in the SIV- macaque model, we will determine if targeting liver macrophages is a potential strategy for immunotherapy in HIV-infected patients.